Colorectal cancer (CRC) is the second leading cause of malignant-associated death in the USA with inflammation as a key driving force for its development, growth, and progression. p38?, a member of p38 mitogen-activated protein kinases (p38 MAPK?? ?? ?, and ?), is oncogenic, pro-inflammatory, and overexpressed in clinical CRC but the role of epithelial p38? in CRC tumorigenesis has not been tested. ?- catenin, a critical cofactor of Wnt transcription, is aberrantly activated in 90% of CRC. And yet, ?-catenin is undruggable and there is thus an urgent need to identify druggable ?-catenin activators for therapeutic intervention. Here we propose that p38? MAPK in intestinal epithelial cells (IEC) drives CRC tumorigenesis by stimulating oncogenic ?-catenin phosphorylation. This hypothesis is based on our preliminary studies showing that: 1) inflammation coordinately stimulates p38? and ?-catenin phosphorylation in CRC cells; 2) p38? directly phosphorylates ?-catenin at S605, which increases ?-catenin stability, the ?-catenin-TCF4 interaction, Wnt transcription and CRC growth; 3) inflammation activates p38?, but not p38?, in intestinal tissues of mice, and IEC-specific p38? knockout (KO) reduces pro-inflammatory cytokine expression and attenuates colitis severity; 4) IEC p38? KO inhibits colon tumorigenesis and p-?-catenin/S605/Wnt signaling in the azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model of colitis-associated cancer (CAC); 5) the p38? pharmacological inhibitor pirfenidone (PFD) suppresses ?-catenin/cytokine expression and colon tumorigenesis in wild-type (WT) mice, but not in p38? KO mice, and further collaborates with the ?-catenin-TCF4 interaction antagonist LF3 and chemotherapeutic drug 5FU to inhibit CRC growth, and 6) p38? is upregulated in clinical CAC specimens and in intestinal tissues of Apcmin and interleukin-10 knockout (IL-10-/-) mice. These results together indicate that IEC p38? is required for tumorigenesis of both CAC and sporadic CRC by stimulating oncogenic ?-catenin phosphorylation. Using genetic and pharmacological approaches, we will test this hypothesis by determining (1) if p38?- induced ?-catenin/S605 phosphorylation stimulates ?-catenin nuclear translocation, ?-catenin-TCF4 interaction, Wnt transcription and CRC growth; (2) if IEC-specific p38? KO blocks tumorigenesis in IL- 10-/- and Apcmin mice and if p38? is essential for the ?-catenin/TCF4/Wnt signaling to promote malignant progression in CRC pathogenesis; and (3) if the p38? pharmacological inhibitor pirfenidone (PFD) blocks CRC tumorigenesis and increases the growth-inhibitory activity of LF3 and 5FU by disrupting the p38?/?-catenin/TCF4/Wnt pathway. Upon completion, these studies will demonstrate if epithelial p38? promotes CRC tumorigenesis by stimulating oncogenic ?-catenin/S605 phosphorylation and Wnt transcription. Demonstrating the effectiveness of PFD in inhibiting Wnt signaling and CRC tumorigenesis by targeting intestinal epithelial p38? will reveal that drugging p38? has a great potential for colon cancer targeted therapy.